Compounds that exhibit cardiotonic properties cause cardiac muscle (in particular, the myocardium) to pump more forcefully and effectively. Cardiotonic agents are often used to treat heart failure because they can relieve one of the early effects of the condition--the buildup of fluid in the body tissues. Blood circulation is also improved.
The administration of a cardiotonic agent provides what is known as a "positive inotropic effect" or an increase in the contractile force of cardiac muscle in a dose-dependent manner. Digitalis is one of the most frequently used cardiotonic agents; other examples include ouabain and strophanthidin.
The administration of vasodilators or vasodilating agents produces a relaxation of the muscles of the blood vessels. This has the effect of enlarging the blood vessel passage, reducing resistance to the flow of blood and lowering the blood pressure. As a result, more blood reaches the tissues. Examples of such agents include nitroglycerin, other nitrates, hydralazine and the like. Renal vasodilators, of course, produce a relaxation of the muscles of blood vessels that are associated with the kidneys.
Phosphodiesterases convert cyclic-AMP (cyclic adenosine monophosphate or "cAMP") to 5'-AMP. Phosphodiesterase fraction III is one example of a biologically active phosphodiesterase. Compounds including theophylline and caffeine inhibit phosphodiesterase activity and its breakdown of cAMP; therefore, a high level of cAMP in the blood is maintained.
Compounds that exhibit cardiotonic and vasodilating properties and which also inhibit the hydrolytic activity of phosphodiesterases would be a substantial improvement over currently available compounds that do not possess each of the foregoing properties.
A number of compounds that are structurally related to isoquinolines and isoquinolinols have been described in the literature.
U.S. Pat. Nos. 3,798,225, 3,910,927 and 4,015,006 to Kreighbaum et al. (Mead Johnson and Co.) relate to 2-substituted-3(2H)-isoquinolones and 2-substituted-3-alkoxyisoquinolines that are reported to have hypotensive and peripheral vasodilating properties upon oral administration. The patents relate in particular to 1-benzyl derivatives of the above compounds.
The preparation of 3-hydroxy-6,7-dimethoxy-1-methylisoquinoline and the corresponding tautomeric form, 6,7-dimethoxy-1-methyl-3(2H)-isoquinolone, which is the parent compound of several compounds of this invention, has been reported along with the preparation of the corresponding 3-ethoxy and 3-acetoxy derivatives. [Bentley et al., J. Chem Soc., 1763 (1952); Dorofeenko et al., USSR Author's Certificate No. 207,921, CA, 69, 52003x (1967); and D. Evans et al., J. Chem Soc. (B), 590 (1967)].
The compounds used as starting materials in this invention are prepared according to the procedures described in our copending application U.S. Ser. No. 871,967 filed on June 9, 1986 all of said procedures being incorporated herein by reference.
1-Phenylisoquinoline derivatives are described in Ger. Offen. DE 3,227,741 which issued to Hoechst AG. The compounds are reported to exhibit antidepressant activity. U.S. Pat. Nos. 4,282,222 and 4,282,223 to Bartmann et al. (assigned to Hoechst A-G) describe isoquinolines including 3-piperidino, 3-piperazino and 3-piperazino N-substituted derivatives that are reported to exhibit antidepressant activity.
U.S. Pat. No. 3,641,032 to Zinnes et al. (Warner-Lambert Company) describes immunosuppressive compositions that include 2-ethyl-3-hydroxy-1(2H)-isoquinolone diphenylcarbamate.
U.S. Pat. No. 3,870,721 to Archibald et al. relates to 4-alkanoylamino isoquinolinediones and 3-alkanoyloxy-4-alkanoylamino isoquinolones. A representative isoquinolinedione which is reported to inhibit blood platelet aggregation is 4-acetamido-1,2,3,4-tetrahydro-1,3-isoquinolinedione.
U.S. Pat. No. 3,954,771 to Geerts et al., which patent is assigned to UCB Society Anonyme, describes a process for the preparation of 2H-3-isoquinolones. The foregoing compounds are described as precursors for the synthesis of 1,4-dihydro-1,4-ethanoisoquinoline-3(2H)ones (described in U.S. Pat. No. 3,781,436) that are reported to be active in the central nervous system (CNS-active) for the treatment of disorders including insomnia and vertigo.
U.S. Pat. No. 4,041,077 to Ghosez et al. (UCB Societe Anonyme) describes the use of N-benzyl-2,2-dimethoxyacetamides in the synthesis of 2H-3-isoquinolones which, in turn, may be used in the synthesis of 1,4-dihydro-1,4-ethano-isoquinolin-3(2H)ones.